Asymmetric catalysis based on chiral phospholanes and hydroxyl phospholanes

ABSTRACT

Chiral phosphine ligands derived from chiral natural products including D-mannitol and tartaric acid. The ligands contain one or more 5-membered phospholane rings with multiple chiral centers, and provide high stereoselectivity in asymmetric reactions.

This application is a Continuation of application Ser. No. 09/992,551filed Nov. 6, 2001 now U.S. Pat. No. 6,727,377, which is a continuationof application Ser. No. 09/377,065, filed on Aug. 19, 1999 now U.S. Pat.No. 6,337,406 and claims priority from U.S. Provisional application Ser.No. 60/097,473, filed on Aug. 21, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to chiral phospholanes derived from naturalproducts, and asymmetric catalysis using these phospholanes.

2. Description of Related Art

Many chiral phosphine ligands have been explored for practicalapplication in asymmetric catalysis, but few chiral ligands or motifsare efficient for the synthesis of commercially useful chiral moleculesin industry.

Among known chiral phosphines, several are made from electron-donatingchiral phospholanes. One example is the Brunner phospholane shown below.Brunner, H., Organometal. Chem. (1987) 328, 71. However, poorenantioselectivities were observed.

The ligands DuPhos™ and BPE have been used effectively for certainasymmetric hydrogenation reactions. See U.S. Pat. Nos. 5,329,015;5,202,493; and 5,329,015; Burk, M. J., J. Am. Chem. Soc. (1991) 113,8518; Burk, M. J., J. Am. Chem. Soc. (1993) 115, 10125; Burk, M. J., J.Am. Chem. Soc. (1996) 118, 5142. These ligands, however, are noteffective for some other asymmetric reactions. Moreover, synthesis ofthese ligands can be difficult, involving a tedious Kolbe reaction.Also, several liquid DuPhos™/BPE ligands are air-sensitive and thereforedifficult to handle.

The chiral phosphine RoPhos and its use in Rh-catalyzed asymmetrichydrogenation have been reported. Holz, J. et al., A. J. Org. Chem.(1998) 63, 8031; EP 0889 048. Chiral phosphine X1 has also beenreported. Carmichael, D. et al., Chem. Commun. (1999) 261. However, thesynthesis is tedious, involving a P stereogenic center.

The inventor has found that it was not possible to make hydroxy analogsof RoPhos using the experimental procedure disclosed in J. Org. Chem.(1998) 63, 8031. A new synthetic route has been developed. Uniqueproperties are associated with hydroxylphospholanes. An efficient routeto these compounds has also been developed by this inventor. Based onthis hydroxylphospholane framework, a polymer chain or a soluble speciessuch as SO₃ ⁻, PO₃ ²⁻, (CH₂CH₂O)_(n)CH₂CH₂OH (n=1, 2, 3) can beintroduced.

SUMMARY OF THE INVENTION

One aspect of the invention is a ligand of formula A, A′, B, B′, C, C′,D, or D′, or the corresponding enantiomer:

Another aspect of the invention is a compound of the formula E:

Another aspect of the invention is a catalyst including one of thecompounds A-E above, wherein the compound is in the form of a complexwith a transition metal.

Another aspect of the invention is a process for preparing a compound offormula B, by reacting a compound of formula B^(x) with a phosphine:

Another aspect of the invention is a process that includes subjecting asubstrate to an asymmetric reaction in the presence of one of theabove-described ligands, wherein said asymmetric reaction is ahydrogenation, hydride transfer, hydrosilylation, hydroboration,hydrovinylation, olefin metathesis, hydroformylation,hydrocarboxylation, allylic alkylation, cyclopropanation, Diels-Alder,Aldol, Heck, [m+n] cycloaddition, or Michael addition reaction.

Accordingly, one advantage of the invention is in providing chiralligands that can be made in large scale from inexpensive naturalproducts such as D-mannitol or tartaric acids. Another advantage is inproviding new chiral ligands A′-D′ in FIG. 3, in which the relativeconfiguration of the four stereogenic centers around the phospholanediffers from A-D.

Yet another advantage is in providing chiral ligands that are solidand/or more air-stable due to added functional groups, and are moreeasily handled compared to air-sensitive liquids such as DuPhos™/BPEligands. Yet another advantage is in providing chiral ligands that havefunctional groups on the phospholanes that can be keystereochemistry-defining groups, such as a hemilabile anchor, a hydrogenbonding source, or a cation binding site through a crown ether. Yetanother advantage is in providing chiral ligands that have additionalfunctional groups on the phospholanes with water-soluble properties anda convenient site to link a polymer support.

Yet another advantage of the invention is in providing catalysts for avariety of asymmetric reactions such as hydrogenation, hydride transferreaction, hydrosilylation, hydroboration, hydrovinylation, olefinmetathesis, hydroformylation, hydrocarboxylation, allylic alkylation,cyclopropanation, Diels-Alder reaction, Aldol reaction, Heck reaction,Baylis-Hillman reaction and Michael addition can be explored based onthese innovative ligand systems.

Yet another advantage of the invention is in providing a variety ofmethods to make both enantiomers of chiral phosphines. BesidesD-mannitol, other chiral pool materials such as D and L-tartaric acidscan also be used as suitable starting materials for ligand synthesis.Only one phospholane enantiomer can be conveniently obtained usingD-mannitol as the starting material while both phospholane enantiomerscan be easily obtained when using D and L-tartaric acids for the ligandsynthesis.

Both the foregoing general description and the following detaileddescription of the invention are exemplary and explanatory only and arenot necessarily restrictive of the claimed invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows new chiral ligands A, A′, B, B′, C, C′, D, and D′ of theinvention.

FIGS. 2A-2F shows the structure of ligand examples L1 to L32.

FIGS. 3A-3C illustrate syntheses of ligands L1 to L32.

FIGS. 4A-4C show syntheses of some chiral 1,4-diols.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used. Other abbreviations well known topersons of skill in the art of asymmetric synthesis are also used inthis specification.

% ee: enantiomeric excess, (% S−% R)/(% S+% R) or (% R−% S)/(% S+% R)

acac: acetylacetonate

Bn: benzyl

COD: 1,5-cyclooctadiene

Cy: cyclohexyl

DBA: dibenzylideneacetone

HMPA: hexamethylphosphoramide

Ipc: isopinocampheyl

MOM: methoxymethyl

Otf: trifluoromethanesulfonate

rt: room temperature

TBDMSCL: t-butyldimethylsilyl chloride

Im: imidazole

The chiral ligands of the present invention may contain alkyl and arylgroups. By alkyl is meant any straight, branched, or cyclic alkyl group.The number of carbons in the alkyl group is not particularly limited.Preferably, alkyl refers to C1-C20, more preferably C1-C8, even morepreferably C1-C4 alkyl groups. Examples of such alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl,and cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and isomers ofheptyl, octyl, and nonyl. Alkyl groups may be substituted withoutparticular restriction, provided that the substituents do not have anadverse effect on the asymmetric reaction, and are inert to the reactionconditions or are thereby converted in a desirable manner. Examples ofsuch substituents include, but are not limited to, aryl, heterocyclo,alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, nitro, amido,and carboxylic ester groups, and any suitable combination thereof.

By aryl is meant any aromatic or heteroaromatic ring, including suchrings fused to other aliphatic, aromatic or heteroaromatic rings.Examples of aromatic rings include, but are not limited to, phenyl,naphthyl, anthryl, fluorenyl, indenyl, and phenanthryl. Heteroaromaticrings may contain one or more heteroatoms, preferably one or more atomsof nitrogen, oxygen, or sulfur. Examples of heteroaromatic ringsinclude, but are not limited to, pyrrole, pyridine, quinoline,isoquinoline, indole, furan, and thiophene. Aryl groups may besubstituted without particular restriction, provided that thesubstituents do not have an adverse effect on the asymmetric reaction,and are inert to the reaction conditions or are thereby converted in adesirable manner. Examples of such substituents include, but are notlimited to alkyl, aryl, heterocyclo, alkoxy, halo, haloalkyl, amino,alkylamino, dialkylamino, nitro, amido, and carboxylic ester groups, andany suitable combination thereof.

The optical purity of the ligand is preferably at least about 85% ee,more preferably at least about 90% ee, more preferably at least about95% ee, even more preferably at least about 98% ee, and even morepreferably about 100% ee.

As is well known to a person skilled in the art of asymmetric synthesis,a chiral ligand can exist as two enantiomers of opposite configuration.A person skilled in the art will recognize that for any given asymmetricreaction, each enantiomer will produce products of oppositeconfiguration from the other, but with the same conversion and opticalpurity. In this specification, ligand and product structures are shownfor one enantiomer for convenience. Of course, the disclosure alsoapplies to the corresponding enantiomers of opposite configuration, anda person skilled in the art can select the appropriate enantiomer toachieve the desired product configuration.

FIG. 1 shows several classes of chiral phospholanes (A, B, C, D, and A′,B′, C′, D′). The difference between A, B, C, D, and A′, B′, C′, D′ is inthe inversion of two chiral centers in the middle of the rings. For eachclass of ligands, enantiomers are also included, which can be madethrough different chiral pools. A and A′ are chiral bidentatephospholanes with four chiral centers. B and B′ are chiral bidentatephospholanes with four chiral centers and linked by a ring in the middleof five membered rings. C, D, C′, D′ are monophospholanes.

Examples of chiral phospholanes according to the invention include, butare not limited to those shown in FIG. 2. Ligand L1 (A) has a benzylprotecting group on the two center hydroxyl groups while ligand L3 has ahydroxyl group. Ligand L2 belongs to class B′ with a cyclic ketyl in thecenter. Ligands L1-L13 contain bridging groups such as CH₂CH₂, benzene,ferrocene, biaryl, binaphthyl groups. Ligands L14-L17 are linked to apolymer backbone. Ligands L18-L21 have water soluble groups. In ligandsL22-L25, an 18-crown-6 group was introduced. Ligands L26-L27 aremonophospholanes containing a variety of groups. Ligands L30-L32 haveadditional groups as substituents of aryls; some will lead to hemilabileligands.

One embodiment of the invention is a compound of formula A, A′, B, B′,C, C′, D, or D′, or the corresponding enantiomer:

wherein:

-   -   a) R and R² are aryl, alkyl, alkyl aryl, or aryl alkyl, which        may be substituted with carboxylic acid, alkoxy, hydroxy,        alkylthio, thiol, dialkylamino, diphenylphosphino, or chiral        oxazolino groups;    -   b) R¹ can be H, alkyl, silane, aryl, a water soluble unit, or a        linked polymer chain or inorganic support;    -   c) the ring component    -    represents a protected diol, a crown ether linkage, —O-alkyl-O—        wherein the alkyl group is linked to a polymer, or        —O—(CH₂CH₂—O)_(n)— wherein the methylene groups are optionally        substituted by C1-C8 alkyl; and    -   d)    -    may be:    -   —(CH₂)_(n)— where n is an integer ranging from 1 to 8;    -   —(CH₂)_(n)X(CH₂)_(m)— wherein n and m are each integers, the        same or different, ranging from 1 to 8, and X is O, S, NR⁴, PR⁴,        AsR⁴, SbR⁴, divalent aryl, divalent fused aryl, divalent        5-membered ring heterocyclic group, or divalent fused        heterocyclic group, wherein R⁴ is hydrogen, aryl alkyl,        substituted aryl or substituted alkyl groups; or    -   1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl or 2,2′-divalent        1,2′binapthyl or ferrocene, each of which may be substituted        with aryl, C1-C8 alkyl, F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂,        OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, or SbR⁵ ₂, wherein:        -   the substitution on 1,2-divalent phenyl, the ferrocene or            biaryl bridge can be independently halogen, alkyl, alkoxyl,            aryl, aryloxy, nitro, amino, vinyl, substituted vinyl,            alkynyl, or sulfonic acids; and        -   R⁵ is hydrogen, C1-C8 alkyl, C1-C8 fluoroalkyl, or C1-C8            perfluoroalkyl, aryl; substituted aryl; arylalkyl;            ring-substituted arylalkyl; or —CR³ ₂(CR³ ₂)_(q)X(CR³            ₂)_(p)R¹ wherein q and p are integers, the same or            different, ranging from 1 to 8; R³ is an aryl, alkyl,            substituted aryl and substituted alkyl group; and R¹ and X            are as defined above.

The term “water soluble unit” means any functional group imparting watersolubility, including, but not limited to, SO₃ ⁻, PO₃ ²⁻; CH₂COO⁻, aquaternary ammonium group attached via an ester or alkyl linkage such asC═O(CH₂)_(x)NAlk₃ or (CH₂)_(x)NAlk₃ where Alk₃ represents three alkylgroups that are independently C1-C4 alkyl and x is 1-4,(CH₂CH₂O)_(n)CH₂CH₂OT (n=1-3) wherein T may be H or CH₃, i.e., PEG orMeO-PEG. The counterion for water soluble units bearing a chargeinclude, but are not limited to, metals such as alkali and alkalineearth metals, and halogens and Otf.

When R¹ is a linked polymer chain, the linker may be any suitablelinking unit commonly used to bind catalysts to polymers or supportmaterials, including, but not limited to, a C1-C6 branched or unbranchedalkyl chain, —C₆H₄CH═CH₂ for polymerization with styrene or othersubstituted vinyl monomer, —C═OCH═CH₂ for polymerization with anacrylate or other substituted vinyl monomer. The polymer may be anypolymer or copolymer, preferably polystyrene or a copolymer of styreneand a substituted vinyl monomer, polyacrylate, PEG or MeO-PEG, ordendritic polymers of polyesters or polyenamides. The preceding alsoapplies to the ring component

as —O-alkyl-O— wherein the alkyl group is linked to a polymer.

When R¹ is a linked inorganic support, examples of inorganic supportsinclude, but are not limited to, silica or zeolites. The inorganicsupport may be linked by any conventional means, including, but notlimited to, attaching —C═ONH(CH₂)_(x)Si(OEt)₃ (where x is 1-4) as linkerand binding through this linker to silica via controlled hydrolysis ofthe Si(OEt)₃ group, where C═ONH may be replaced by any other functionalgroup suitable for connecting the methylene chain of the linker to thephospholane oxygen.

When the ring component

is a protected diol, a person of skill in the art will recognize thatany number of the diol protecting group may be used, e.g., thosedescribed in Greene and Wuts, Protective Groups in Organic Synthesis,1991, John Wiley & Sons, and MacOmie, Protective Groups in OrganicChemistry, 1975, Plenum Press, the entire contents of which areincorporated herein by reference. A suitable diol protecting group maybe deprotected under conditions that do not significantly degrade therest of the molecule. Examples of diol protecting groups include, butare not limited to acetals and ketals.

In one variant, the invention is a compound of formula A or A′, or thecorresponding enantiomer. Preferably, in the compound of formula A orA′, or the corresponding enantiomer, R is methyl, ethyl, or benzyl, R¹is hydrogen or benzyl, and

is —(CH₂)_(n)— where n is an integer ranging from 1 to 3, 1,2-divalentphenyl; 2,2′-divalent 1,1′biphenyl, 2,2′-divalent 1,2′binapthyl, orferrocene, each of which may be substituted with alkyl having 1-3 carbonatoms; or OR⁵, wherein R⁵ is methyl or ethyl.

Examples of the compound of formula A or A′ include, but are not limitedto L1, L3-L5, L7-L8, L10-L12, and L18-L21, and the correspondingenantiomers, and the compound of formula 2 below and its enantiomer.

In another variant, the invention is a compound of formula B or B′, orthe corresponding enantiomer. Preferably, in the compound of formula Bor B′, or the corresponding enantiomer, R is C1-C4 alkyl, unsubstitutedor substituted by phenyl or OR⁵, wherein R⁵ is C1-C2 alkyl, and the ringcomponent

is —O—CR^(a)R^(b)—O—, wherein R^(a) is hydrogen or C1-C4 alkyl and R^(b)is an alkyl or aryl linker attached to a polymer.

Examples of the compound of formula B or B′ include, but are not limitedto L2, L6, L9, L13, L14-L17, and L22-L25, and the correspondingenantiomers, and the compound of formula 3 below and its enantiomer:

In another variant, the invention is a compound of formula C, D, C′, orD′, or the corresponding enantiomer. Preferably, in the compound offormula C, D, C′, or D′, or the corresponding enantiomer, R is methyl,ethyl, or benzyl; R¹ is hydrogen or benzyl; R² is o-X-phenyl wherein Xis a carboxylic acid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino,diphenylphosphino, or chiral oxazolino group; and the ring component

is —O—CR^(a)R^(b)—O—, wherein R^(a) and R^(b) are independently hydrogenor C1-C4 alkyl.

Examples of the compound of formula B or B′ include, but are not limitedto structures L26-L32, and the corresponding enantiomers, and thecompound of formula 1 below and its enantiomer:

Another embodiment of the invention is a compound of formula E or thecorresponding enantiomer.

wherein:

R and R⁹ are aryl, C1-C8 alkyl, C1-C8 alkyl aryl, or aryl C1-C8 alkyl,which may be substituted with carboxylic acid, alkoxy, hydroxy,alkylthio, thiol, dialkylamino; diphenylphosphino, or chiral oxazolinogroups; and

W is boron, phosphorus, or silicon, or W and R⁹ together form C═O orSO₂.

Preferably, in the compound of formula E or the correspondingenantiomer, R is C1-C4 alkyl and R⁹ is C1-C4 alkyl or phenyl.

Another embodiment of the invention is a catalyst including any of thecompounds described in the embodiments above, wherein the compound is inthe form of a complex with a transition metal. In principle, anytransition metal may be used. Preferably, the transition metal is aGroup VIII transition metal. More preferably, the transition metal isrhodium, iridium, ruthenium, nickel, or palladium. Preferably, thecompound is in the form of a complex with Pd₂(DBA)₃, Pd(OAc)₂;[Rh(COD)Cl]₂, [Rh(COD)₂]X, Rh(acac)(CO)₂; RuCl₂(COD),Ru(COD)(methylallyl)₂, Ru(Ar)Cl₂, wherein Ar is an aryl group,unsubstituted or substituted with an alkyl group; [Ir(COD)Cl]₂,[Ir(COD)₂]X; or Ni(allyl)X; wherein X is a counterion. The counterion Xmay generally be any suitable anion for use in asymmetric synthesis. Aperson of skill in the art can readily determine what such a suitablecounterion would be for any particular set of ligands, reactionconditions and substrates. Examples of suitable counterions include, butare not limited to, halogen ions (including Cl⁻, Br⁻, and I⁻), BF₄ ⁻,ClO₄ ⁻, SbF₆ ⁻, CF₃SO₃ ⁻, BAr₄ ⁻ (wherein Ar is aryl), and Otf⁻(trifluoromethanesulfonate). Preferably, X is BF₄, ClO₄, SbF₆, orCF₃SO₃. Preferably, the catalyst comprises Ru(RCOO)₂(diphosphine),RuX₂(diphosphine), Ru(methylallyl)₂(diphosphine), or Ru(arylgroup)X₂(diphosphine), and X is halogen.

A non-limiting example of the invention is a catalyst for asymmetrichydrogenation of ketones, imines, and olefins, that includes Rhcomplexes [Rh(COD)Cl]₂, [Rh(COD)₂]X (X=BF₄, ClO₄, SbF₆, CF₃SO₃, etc.)]with 2 or 3:

Another embodiment of the invention is a process including subjecting asubstrate to an asymmetric reaction in the presence of a catalystcomprising a chiral ligand according to claim 1, wherein said asymmetricreaction is a hydrogenation, hydride transfer, hydrosilylation,hydroboration, hydrovinylation, olefin metathesis, hydroformylation,hydrocarboxylation, allylic alkylation, cyclopropanation, Diels-Alder,Aldol, Heck, [m+n] cycloaddition, or Michael addition reaction.Preferably, the process includes asymmetric hydrogenation of a ketone,imine, enamide, or olefin.

Another embodiment of the invention is a process for preparing acompound of formula B, comprising reacting a compound of formula B^(x)with a phosphine:

wherein:

the phosphine is

a) R is aryl, alkyl, alkyl aryl, or aryl alkyl, which may be substitutedwith carboxylic acid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino,diphenylphosphino, or chiral oxazolino groups;

b) the ring component

represents a protected diol, a crown ether linkage, or —O—CH₂CH₂)_(n)—O—wherein n is an integer ranging from 1 to 8 and the methylene groups areoptionally substituted by alkyl or linked to a polymer; and

c)

may be:

—(CH₂)_(n)— where n is an integer ranging from 1 to 8;

—(CH₂)_(n)X(CH₂)_(m)— wherein n, m are each integers, the same ordifferent, ranging from 1 to 8; or

1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl or 2,2′-divalent1,2′binapthyl or ferrocene, each of which may be substituted with arylor substituted aryl, or alkyl having 1-8 carbon atoms, heteroatom groupssuch as F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂,AsR⁵ ₂, or SbR⁵ ₂, wherein:

-   -   the substitution on 1,2-divalent phenyl, the ferrocene or biaryl        bridge can be independently halogen, alkyl, alkoxyl, aryl,        aryloxy, nitro, amino, vinyl, substituted vinyl, akkynyl, or        sulfonic acids; and    -   R⁵ is hydrogen, C1-C8 alkyl, C1-C8 fluoroalkyl, or C1-C8        perfluoroalkyl, aryl; substituted aryl; arylalkyl;        ring-substituted arylalkyl; or —CR³ ₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹        wherein q and p are integers, the same or different, ranging        from 1 to 8; X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl,        divalent fused aryl, divalent 5-membered ring heterocyclic        group, or divalent fused heterocyclic group, wherein R³ and R⁴        are aryl, alkyl, substituted aryl and substituted alkyl groups.

Preferably, R is C1-C4 alkyl; the ring component

represents a protected diol; and

is unsubstituted or substituted 1,2-divalent phenyl. More prefarbly, Ris methyl or ethyl, the ring component

is —O—C(CH₃)₂—O—, and

is unsubstituted 1,2-divalent phenyl.

FIGS. 3A-3C show several pathways for the synthesis of compounds shownin FIGS. 2A-2F. The chiral 1,4-diols used in the synthesis of ligandsL1-L32 can be derived from D-mannitol and related compounds. A number ofthese diols have been reported in the literature. The procedure for thesynthesis of L1(A), L3(A) and L8 (A′) is outlined in FIGS. 3A-3B; keyintermediates L35 and L35′ have been reported in the literature(Poitout, L.; Tetrahedron Letter (1994) 35, 3293). The epoxide openingstep from L35 to L37 in FIG. 3A has also been reported (Nugel, S. et al.J. Med. Chem. (1996) 39, 2136). Formation of cyclic sulfates can be doneaccording Sharpless' procedure (Kim, B. M., Tetrahedron Letters (1989)30, 655). The last step is similar as the synthesis of DuPhos™ (Burk,U.S. Pat. Nos. 5,329,015; 5,202,493; and 5,329,015; Burk, M. J., J. Am.Chem. Soc. (1991) 113, 8518; Burk, M. J., J. Am. Chem. Soc. (1993) 115,10125; Burk, M. J., J. Am. Chem. Soc. (1996) 118, 5142). In the step toform L37, other nucleophiles such as CH₃ ⁻, Cy⁻ can be applied otherthan Ph⁻. Intermediate L36 can be obtained easily. In principle, ketylcan be formed from L3(A) to give class B compounds.

When para-vinyl benzaldehyde is used as the protecting group,polymerization under polystyrene forming conditions should yieldcompound L17 (B), shown in FIG. 2C.

Instead of using a benzyl protecting group, 18-crown-6 or water solublegroups can be linked to form compounds such as L19 (A) or L25 (B), asshown in FIGS. 2D and 2E, respectively.

Another epoxide L39 has been studied extensively for the synthesis ofHIV protease inhibitors (Ghosh, A. K., Tetrahedron Lett. (1991) 32,5729. and Nugel, S. et al., J. Med. Chem. (1996) 39, 2136). Compound L40is known and conversion of this intermediate to L9 (B) is expected.Finally, intermediate L41 and L38 can be converted to L29 (C) asillustrated in FIG. 3C.

FIGS. 4A-4C outline some useful synthetic procedures, which was recentlydisclosed in the literature. Instead of using D-mannitol as the startingmaterial, which can only lead to one enantiomer of the chiral phosphine,preparation of chiral diols from either D or L-tartaric ester can resultin formation of either of two enantiomers. Using these reportedprocedures (Nugel, S. et al. J. Med. Chem. (1996) 39, 2136; Colobert, F.J. Org. Chem. (1998) 63, 8918; and Iwasaki, S. Tetrahedron Lett. (1996)37, 885), several chiral 1,4-diols can be obtained, as shown in FIGS.4A-4C.

The present invention is further illustrated by the following examples,which are designed to teach those of ordinary skill in the art how topractice the invention. The following examples are illustrative of theinvention and should not be construed as limiting the invention asclaimed.

EXAMPLES

Synthesis of Phospholane Ligands

The hydroxyl phosphine ligands 1, 2, and 3 were synthesized successfullyin high yield using familiar procedures. They are white solids. Thesynthetic route is exemplified below.

Compound 10 is a nice colorless crystal and can be recrystallized fromethyl ehter and methanol. Compound 2 was used directly after removal ofthe reaction solvent without any purification. An advantage of thisroute is that there is no need to run column chromatography forpurification.

Compound 14 is a colorless crystal and can be recrystallized from ethylether and methanol.

Compound 3 was used directly after removal of the reaction solventwithout any purification. There is no need to run a column in thissynthetic route. Ring opening of 11 with other nucleophiles R₂CuLi(R=Ph, Et, iPr etc.) leads to a series of compounds.

The cyclic sulfate 15 was also made from the corresponding alcohol,which was synthesized in the same procedure to make 12.

Ligand 16 can be made in a similar manner using the same procedure asfor the synthesis of 2 and 3.

Compound 18 was prepared by stirring 1 and phenylboronic acid inmethylene chloride. After removal of the solvent, it was used directlyin asymmetric reaction.

Compound 19 was prepared from cyclic sulfate 9. Acid catalytichydrolysis afforded the hydroxylphosphine 1 in high yield (>90%).

Compound 21 was prepared from known cyclic sulfate 20. Several chiralmonophospholanes from D-mannitol (e.g., 19, 21) are made and manymethods cleave the protecting groups to give hydroxylphospholane 1. Theiso-propylene group in 19 was smoothly removed by an acid catalyzedhydrolysis. However, the borane adduct of 21 was just selectivelydebenzylated when BCl₃ or BF₃.Et₂O was used as the reagent to give thederivatives bearing one hydroxyl and one benzyl ether group.Hydrogenation of 21 using Pd/C catalyst does not give the desiredhydroxyl phospholane product 1. The corresponding phosphine oxide of 21also gave selectively debenzylated products under mild hydrogenationconditions (10% Pd(OH)₂/C). The hydrogenation reaction done under hightemperature (50° C.) and H₂ pressure (40 atm) not only cleaved thebenzyl ether but also reduced the phenyl group to a cyclohexyl group.

General Experimental Procedure

Unless otherwise indicated, all reactions were carried out undernitrogen. THF and ether were freshly distilled from sodium benzophenoneketyl. Toluene were freshly distilled from sodium. Dichloromethane andhexane were freshly distilled from CaH₂. Methanol was distilled frommagnesium and CaH₂. Reactions were monitored by thin-layerchromatography (TLC) analysis. Column chromatography was performed usingEM silica gel 60 (230-400 mesh).

¹H NMR were recorded on Bruker ACE 200, WP 200, AM 300 and WM 360spectrometers. Chemical shifts are reported in ppm downfield fromtetramethylsilane with the solvent resonance as the internal standard(CDCl₃, δ 7.26 ppm). ¹³C, ³¹P and ¹H NMR spectra were recorded on BrukerAM 300 and WM 360 or Varian 200 or 500 spectrometers with completeproton decoupling. Chemical shifts are reported in ppm downfield fromtetramethylsilane with the solvent resonance as the internal standard(CDCl₃, δ 77.0 ppm). Optical rotation was obtained on a Perkin-Elmer 241polarimeter. MS spectra were recorded on a KRATOS mass spectrometer MS9/50 for LR-EI and HR-EI. GC analyses were carried out on aHewlett-Packard 5890 gas chromatograph with a 30-m Supelco β-DEX™column. HPLC analyses were carried out on a Waters™ 600 chromatographwith a 25-cm CHIRALCEL OD column.

Example 1 Phosphine 19

To a stirred solution of phenylphosphine (0.44 g, 4.0 mmol) in THF (80mL), n-BuLi (1.6 M n-hexane solution, 2.5 mL, 4.0 mmol) was addeddropwise via a syringe at −78° C. The resulting pale yellow solution wasstirred for further 2 h at room temperature. After cooling the mixtureto −78° C., cyclic sulfate 9 (1.01 g, 4.0 mmol) in THF (40 mL) was addedover 10 min. The resulting yellow solution was warmed to roomtemperature and stirred for 4 h. After cooling to −78° C., n-BuLi (1.6 Msolution in n-hexane, 2.5 mL, 4.0 mmol) was added, and the reactionmixture was stirred for an additional 20 h at room temperature. Thecolor of the reaction mixture changed from orange yellow to red, andthen decolorized to colorless. After removal of the solvent underreduced pressure, the residue was dissolved in 40 mL of ethyl ether, and30 mL of brine was added. The aqueous layer was then washed with 3×30 mLethyl ether. The combined organic layers were dried over Na₂SO₄ andconcentrated to afford a colorless oil. This oil can be further purifiedby a short silica gel column eluted with hexane/ether (9:1), ¹H NMR(CDCl₃): δ 7.72-7.27 (m, 5H, aromatic), 4.60-4.32 (m, 2H), 2.70-2.51 (m,2H), 1.52 (s, 6H), 1.38-1.32 (m, 3H), 0.70-0.52(m, 3H). ³¹P NMR (CDCl3):δ 50.2 ppm.

Example 2 Phosphine 1

Phosphine 19 obtained above was dissolved in 50 mL methanol and 2 mL ofwater. To this solution, 0.05 mL of methanesulfonic acid was added andthe resulting mixture was refluxing for 10 h. The solvent was removedunder reduced pressure and the residue was dissolved in 50 mL ofmethylene chloride. 30 mL of aq NaHCO₃ was added and the two layers wereseparated. The aqueous layer was washed with 3×40 mL of methylenechloride. The combined organic layers were dried over Na₂SO₄ andconcentrated to give a white solid, compound 1.

Example 3 Phosphine 21

To a stirred solution of phenylphosphine (220.2 g, 2.0 mmol) in THF (50mL), n-BuLi (1.6 M n-hexane solution, 1.25 mL, 2.0 mmol) was addeddropwise via a syringe at −78° C. Then the resulting yellow solution wasstirred for further 2 h at room temperature. After cooling the mixtureto −78° C., cyclic sulfate 20 (0.78 g, 2.0 mmol) in THF (30 mL) wasadded over 10 min. The resulting brown solution was warmed to roomtemperature and stirred for 4 h. After cooling to −78° C., n-BuLi (1.6 Msolution in n-hexane, 1.25 mL, 2.0 mmol) was added and the reactionmixture was stirred for an additional 20 h at room temperature. ThenBH₃-THF complex (1M solution in THF, 3.0 mL, 3.0 mmol) was added at 0°C. After stirring overnight, the solvents were removed under reducedpressure. Water (30 mL) was added to the residue and the aqueoussolution extracted with CH₂Cl₂ (3×40 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated to afford the crudephospholane-borane as a colorless syrup. Purification was performed byflash chromatography (hexanes/AcOEt=9:1) to give the 21-borane adduct asa white solid (767 mg, 92%). ¹H NMR (CDCl₃): δ 7.87-7.82 (m, 2H,aromatic), 7.31-7.16 (m, 3H, aromatic), 4.56-4.42 (m, 4H), 4.02-3.90 (m,2H), 2.78-2.72 (m, 2H), 1.22-1.16 (m, 3H), 0.85-0.79 (m, 3H), 1.23-0(broad, 3H, BH₃). ¹³C NMR (CDCl₃): δ 138.0, 137.6, 134.5, 134.4, 131.1,128.5-126.4, 83.7, 83.4, 72.6, 72.3, 36.2, 35.8, 9.2, 9.1. ³¹P NMR(CDCl₃): δ 37.1, b, ppm. The 21-borane adduct was dissolved in 20 mL oftoluene and 2 equivalent of DABCO was added. The resulting mixture washeated at 50° C. for 8 h. After removal of the solvent, the residue waspassed through a plug of silica gel eluted with hexane/ethyl acetate(9:1) to afford phosphine 21 as a colorless oil. ³¹P NMR (CDCl₃): δ 3.8ppm.

Example 4 Phosphine 10

To a stirred solution of 1,2-bis(phosphino)benzene (1.24 g, 8.72 mmol)in THF (200 mL), n-BuLi (1.6 M n-hexane solution, 10.9 mL, 17.4 mmol)was added dropwise via a syringe at −78 □C. Then the resulting yellowsolution was stirred for further 2 h at room temperature. After coolingthe mixture to −78 □C, cyclic sulfate 9 (4.39 g, 17.4 mmol) in THF (50mL) was added over 10 min. The resulting yellow solution was warmed toroom temperature and stirred for 4 h. After cooling to −78□ C., n-BuLi(1.6 M solution in n-hexane, 11.0 mL, 17.5 mmol) was added, and thereaction mixture was stirred for additional 20 h at room temperature.After removal of the solvent under reduced pressure, the residue wasdissolved in 50 mL of ethyl ether, and 50 mL of brine was added. Theaqueous layer was then washed with 3×40 mL ethyl ether. The combinedorganic layers were dried over Na₂SO₄ and concentrated to afford acolorless crystal. This crystal was further recrystallized fromether/methanol. ¹H NMR (CDCl₃): δ 7.38-7.33 (m, 4H, aromatic), 4.46-4.36(m, 4H), 2.89-2.82 (m, 2H), 2.56-2.51 (m, 2H), 1.47 (s, 6H), 1.42 (s,6H), 1.33-1.28 (m, 6H), 0.73-0.69 (m, 6H); ¹³C NMR (CDCl₃): δ 140.53,130.59, 129.00, 117.44, 81.41, 80.51 (t, J_(PC)=6.5 Hz), 27.34, 27.30,25.05 (t, J_(PC)=10.3 Hz), 24.20, 13.74 (t, J_(PC)=19.6 Hz), 12.15; ³¹PNMR (CDCl₃): δ 45.1 ppm. HRMS calcd for C₂₄H₃₇O₄P₂ (MH⁺) 451.2167; found451.2164.

Example 5 Phosphine 2

Phosphine 10 obtained above was disolved in 100 mL of methanol and 2 mLof water. 0.1 mL of methanesufonic acid was added and the resultingmixturing was refluxing for 10 h. After removal of the solvent theresidue was passed through a short plug of silica gel eluted with ethylacetate/methanol (95:5) to give compound 2 as a white solid. ¹H NMR(CD₃OD): δ 8.42-8.07 (m, 2H, aromatic), 7.72-7.69 (m, 2H, aromatic),4.24-4.17 (m, 4H), 3.31-3.28 (m, 2H), 3.16-3.13 (m, 2H), 1.37-1.30 (m,6H), 0.94-0.88 (m, 6H); ¹³C NMR (CD₃OD): δ 136.6 (t, J_(PC)=3.4 Hz),133.7, 133.6, 80.2, 80.0, 37.3, 35.4 (d, J_(PC)=10.0 Hz), 11.6 (d,J_(PC)=6.5 Hz), 10.8. ³¹P NMR (CD₃OD): δ 11.9 (broad) ppm. HRMS calcdfor C₁₈H₂₉O₄P₂ (MH⁺) 371.1541; found 371.1523.

Example 6 Phosphines 14 and 3

Phosphine 14 was prepared using the similar procedure for 10 andrecrystallized from ethyl ether/methanol as a colorless crystal. ¹H NMR(CDCl₃): δ 7.41-7.32 (m, 4H, aromatic), 4.50-4.37 (m, 4H), 2.62-2.61 (m,2H), 2.22-2.20 (m, 2H), 2.19-2.17 (m, 2H), 1.50-1.44 (m, 2H), 1.47 (s,6H), 1.32-1.30 (m, 2H), 0.99-0.95 (m, 6H), 0.88-0.86 (m, 2H), 0.79-0.75(m, 6H); ¹³C NMR (CDCl₃): δ 141.3, 131.1, 129.2, 117.1, 82.3, 81.4(t,=6.1 Hz), 33.0, 32.8 (t,=9.6), 27.4, 27.3, 21.4, 21.1 (t,=14.2),14.6, 13.1 (t,=5.1 Hz).; ³¹P NMR (CDCl₃): δ 34.5 ppm. Catalytic acidhydrolysis give phosphine 3.

Example 7 General Procedure for Asymmetric Hydrogenation

To a solution of [Rh(COD)₂]X (X=counterion) (5.0 mg, 0.012 mmol) in THF(10 mL) in a glovebox was added chiral ligand (0.15 mL of 0.1 M solutionin toluene, 0.015 mmol). After stirring the mixture for 30 min, thedehydroamino acid (1.2 mmol) was added. The hydrogenation was performedat room temperature under hydrogen for 24 h. The reaction mixture wastreated with CH₂N₂, then concentrated in Vacuo. The residue was passedthrough a short silica gel column to remove the catalyst. Theenantiomeric excesses were measured by GC using a Chirasil-VAL III FSOTcolumn. The absolute configuration of products was determined bycomparing the observed rotation with the reported value. All reactionswent in quantitative yield with no by-products found by GC.

Example 8 General Procedure for the Baylis-Hillman Reaction

The mixture of 4-pyridinecarbonaldehyde (1 mmol) and 1 mL of methylacrylate was degassed three times by a freeze-thaw method, and then theresulting solution was transferred into another Schlenk tube containing10% catalyst. The solution was stirred at room temperature for some timeand the methyl acrylate was removed under vaccm. The residue waspurified by a flash chromatograph eluted with hexanes/ethyl acetate(1:2). The enantiomeric excess was measured by capillary GC.

Asymmetric Baylis-Hillman Reaction

TABLE 1 Catalytic Baylis-Hillman Reaction

Run Catalyst Reaction Time Yield (%) % ee 1 21 70 h 29 19 2  1  9 h 8317 3 18 31 h 56 18

The reaction was accelerated significantly when hydroxylphosphine wasused as catalyst. For example, the reaction takes 70 h and gives loweryield (29%) with benzyl protected hydroxylphospholane 21 as catalyst,while the same reaction proceeds in 9 h and offers high yield (83%) withhydroxylphospholane 1. This demonstrates the importance of the hydroxylgroup in the catalytic system.

Hydrogenation of Dehydroamino Acids

TABLE 2 Asymmetric Hydrogenation of Dehydroamino Acid Derivatives^(a)

Run Substrate Ligand % ee^(b) Ligand % ee 1 R = H, R′ = H 2 >99^(c)3 >99 2 R = H, R′ = CH₃ 2  98.3 3 99 3 R = Ph, R′ = H 2 >99^(c) 3 >99 4R = Ph, R′ = CH₃ 2 >99 3 >99 5 R = p-F—Ph, R′ = H 2  98.5^(c) 3 >99 6 R= p-F—Ph, R′ = CH₃ 2  98.4 3 >99 7 R = p-MeO—Ph, R1 = H 2  98.1^(c,d) 399 8 R = p-MeO—Ph, R′ = CH₃ 2  98.3^(d) 3 >99 9 R = 2-thienyl, R′ = H 2>99^(c) 3 >99 10 R = 2-thienyl, R′ = CH₃ 2 >99 3 >99 11 R = m-Br—Ph, R′= H 3 99 12 R = m-Br—Ph, R′ = CH₃ 3 >99 13 R = o-Cl—Ph, R′ = H 3 98 14 R= o-Cl—Ph, R′ = CH₃ 3 98 15 R = 2-naphthyl, R′ = H 3 >99 16 R =2-naphthyl, R′ = CH₃ 3 >99 17 R = Ph, R′ = H, benzonate 3 >99 18 R = Ph,R′ = CH₃, benzonate 3 >99 ^(a)The reaction was carried out at rt under 3atm (45 psi) of H₂ for 12 h in 3 mL of methanol with 100% conversion[substrate (0.5 mmol):[Rh(COD)₂]PF₆:ligand 4 = 1:0, 01:0.011]. ^(b)The Sabsolute configurations were determined by comparing optical rotationswith reported values. The % ee was determined by GC using a Chiral-VALIII FSOT column. ^(c)Determined on the corresponding methyl ester.^(d)The % ee was determined by HPLC using a Chiral OJ column.Catalytic Asymmetric Hydrogenation of Itaconic Acid Derivatives

TABLE 3 Asymmetric Hydrogenation of Itaconic Acid Derivatives

Run Substrate Ligand % ee Ligand % ee^(a) 1 R = H 2 95.7 3 >99 2 R = CH₃2 97.5 3 >99 3 R = CH₃  3^(b) >99 ^(a)Determined by GC using a gamma-225column at 100° C. ^(b)Run in 3:97 MeOH/H₂O instead of neat MeOH. VariousMeOH/H₂O ratios gave comparable results.Catalytic Asymmetric Hydrogenation of Enamides

TABLE 4 Asymmetric Hydrogenation of Enamides

Run Substrate Ligand % ee 1 Ar = Ph, R = H 3 95.8 2 Ar = p-MeO—Ph, R = H3 95.3 3 Ar = p-F₃C—Ph, R = H 3 98.1 4 Ar = p-Cy—Ph, R = H 3 97.7

Example 9 Asymmetric Hydrogenation Using Ligand 24

The Synthetic route to ligand 24 is shown in Scheme 1. From aninexpensive and commercially available starting material, D-mannitol,the important intermediate 1,4-diol cyclic sulfate 9 was preparedaccording to the reported method. See Li, W. et al., Tetrahedron Letter(1999) 40, 6701; Li, W. et al., J. Org. Chem. (2000) 65, 3489; Yan, Y.-Yet al., Org. Letter (2000) 2, 199; Yan, Y.-Y et al., J. Org. Chem (2000)65, 900; Merver, Y. L. et al, Heterocycles (1987) 25, 541; Allevi, P. etal., Tetrahedron: Asymmetry (1994) 5, 927; Gao, Y. et al., J. Am. Chem.Soc. (1988) 110, 7538; Kim, B. M. et al., Tetrahedron Letter (1989) 30,655; Holz, J. et al., J. Org. Chem (1998) 63, 8031; Carmichael, D. etal., Chem. Commun. (1999) 261. The 1,1′-bis(phosphino)ferrocene wasprepared from ferrocene through a two-step procedure. See Burk, M. J. etal., Tetrahedron Letter (1994) 35, 9363. Nucleophilic attack of 9 with1,1′-bis(phosphino)ferrocene in the presence of n-BuLi affords ligand24. ¹H NMR (360 MHz, C₆D₆) δ 4.55-4.50 (m, 2H), 4.34-4.29 (m, 2H),4.14-4.12 (m, 4H), 4.05 (m, 2H), 3.72 (m, 2H), 2.38-2.30 (m, 4H),1.51-1.44 (m, 18H), 0.80-0.76 (m, 6H); ¹³C NMR (400 MHz, C₆D₆) δ 117.6(s), 82.3-82.2 (m), 77.4 (d, J_(cp)=37.3 Hz), 75.2 (d, J_(cp)=25.3 Hz),72.3 (d, J_(cp)=44.8 Hz), 70.3-70.4 (m), 27.7 (s), 27.6 (s), 26.6-26.4(m), 14.3 (s), 14.0 (s), 11.2 (s); ³¹P NMR (360 MHz, C₆D₆) δ 39.3; mp152-154° C.; HRMS: m/z calcd for C₂₈H₄₀O₄P₂Fe (M⁺) 559.1829, found559.1846. The new ligand can be easily purified by running columnchromatography in dry-box to give an orange solid in an acceptableyield.

The Rh(I)-catalyzed hydrogenation of dehydroamino acids and their esterderivatives was performed with ligand 24. The catalytic complex wasprepared in situ by mixing Rh(COD)₂ PF₆ and 24 in solvent. Thecommercially available α-(N-acetamido)acrylate 25a was chosen to screenthe reaction conditions. The results are shown in Table 5. Excellentenantioselectivity (over 99% ee) was observed for this reaction. Thisresult is superior to those obtained with ligand 22 (83% ee) and ligand23 (94% ee). No solvent effect was found. This system works very well inboth polar and non-polar solvents (entries 5-8). In decreasing the H₂pressure from 45 psi to 20 psi and reducing the reaction time to 30 min,no deterioration was observed with respect to either conversion orenantioselectivity. This indicates that this catalytic system is notonly highly enantioselective but also highly efficient.

TABLE 5 Rh(I)-24 Catalyzed Asymmetric Hydrogenation ofα-(N-acetamido)acrylate 25a^(a)

Entry Ligand Solvent Pressure of H₂ (psi) Time (h) ee (%)^(f)  1^(c)22a^(e) MeOH 60 ≧6 64  2^(c) 22b^(e) MeOH 60 ≧6 83  3^(d) 23a^(e) MeOH60 18 69  4^(d) 23b^(e) MeOH 60 18 94 5 6 MeOH 45 3 >99 6 6 DCM 45 3 >997 6 THF 45 3 >99 8 6 Toluene 45 3 >99 9 6 MeOH 45 0.5 >99 10  6 MeOH 200.5 >99 ^(a)Hydrogenation Conditions: The reaction was carried at rt. Insitu catalyst, [Rh(COD)₂PF₆](1.0 mol %) and 24 (1.1 mol %), was stirredfor 15 min prior to introduction of substrate and H₂. The reaction wentwith 100% conversion. ^(b)The S absolute configration was assigned bycomparison of optical rotation with reported data. ^(c)See Berens, U. etal., Angew. Chem. Int. (2000) 39. 1981. ^(d)See Marinetti, A. et al.,Synlett (1999) 12, 1975. ^(e)Ligand 22a R = Me; 22b R = Et; 23a R = Me;23b R = i-Pr. ^(f)Enantiomeric excesses were determined by chiral GCusing a Chirasil-VAL III FSOT column.

Table 6 summarizes the results of Rh(I)-24 complex catalyzedhydrogenation of different dehydroamino acids and some ester derivatives25. For most tri-substituted dehydroamino acids and esters, highselectivity was achieved (95-99% ee). One exception was the substrate inwhich R=p-MeO-phenyl (entry 9), only 88.3% ee was obtained, and thereaction was not complete after 3 h, which is normally enough for mostsubstrates. Tetra-substituted dehydroamino acid was also explored (entry16), but the ee value (88.8%) was a little lower than those for thetri-substituted substrates. Irregardless, the overallenantioselectivities for the Rh(I)-24 catalyzed hydrogenation ofdehydroamino acid derivatives were quite good and comparable with thoseattained with the best chiral bisphosphine systems, especially whenconsidering that among the current C₂-symmetric ferrocenyl-bisphosphineligands, these results are among the best reported to date. SeeMarinetti, A. et al., Synlett (1999) 12, 1975; Berens, U. et al., Angew.Chem. Int. (2000) 39, 1981; Sawamura, M. et al., J. Am. Chem. Soc.(1995) 117, 9602; Kang, J. et al., Tetrahedron Letter (1998) 39, 5523;Perea, J. J. A. et al., Tetrahedron Letter (1998) 39, 8073; Perea, J. J.A. et al., Tetrahedron: Asymmetry (1999) 10, 375; Nettekoven, U. et al.,J. Org. Chem. (1999) 64, 3996.

TABLE 6 Rh(I)-24 Catalyzed Asymmetric Hydrogenation of Dehydroamino AcidDerivatives^(a)

Entry Substrate ee (%)^(c) 1 R = H, R′ = H >99^(d) 2 R = H, R′ = CH₃ >993 R = i-Pr, R′ = H >99^(d) 4 R = Ph, R′ = H  94^(d) 5 R = Ph, R′ = CH₃ 96 6 R = p-F—Ph, R′ = H  95^(d) 7 R = p-F—Ph, R′ = CH₃  95 8 R =p-MeO—Ph, R′ = H 9 R = p-MeO—Ph, R′ = CH₃  88^(e,f) 10 R = o-Cl—Ph, R′ =H 11 R = o-Cl—Ph, R′ = CH₃  97 12 R = m-Br—Ph, R′ = H  98^(d) 13 R =m-Br—Ph, R′ = CH₃  97 14 R = 2-naphthyl, R′ = H  98^(d) 15 R =2-naphthyl, R′ = CH₃  97 16

 89 ^(a)Hydrogenation Condition: The reaction was carried at rt under 45psi of H2 for 3-6 h. In situ catalyst, [Rh(COD)₂PF₆] (1.0 mol %) and 6(1.1 mol %), was stirred for 15 min prior to introduction of substrateand H₂. The reaction went with 100% conversion. ^(b)The S absoluteconfiguration was assigned by comparison of optical rotation withreported data. ^(c)Enantiomeric excesses were determined by chiral GCusing a Chirasil-VAL III FSOT column. ^(d)Determined on thecorresponding methyl ester. ^(e)The % ee was determined by HPLC using aDaicel Chiralcel OJ column. ^(f)The reaction was not complete asindicated by TLC after 3 h.

Hydrogenation of itaconic acid derivatives was also preliminarilyexplored with the same catalytic system as above. The reaction wascarried at rt under 80 psi of H² for 12 h. In situ catalyst, [Rh(COD)₂PF₆] (1.0 mol %) and 24 (1.1 mol %), was stirred for 15 min prior tointroduction of substrate and H₂. The reaction went with 100%conversion. The R absolute configuration was assigned by comparison ofoptical rotation with reported data. Enantiomeric excesses weredetermined on the corresponding dimethyl ester by chiral GC using agama-225 column. Excellent results, 99% ee and 96% ee were achieved foritaconic acid 27a and its derivative 27b, respectively.

Example 10 Asymmetric Allylic Alkylation Using Ligands Me-f-KetalPhos(24). Et-f-KetalPhos (28) and Me-KetalPhos (10)

Palladium compounds with chiral ligands f-KetalPhos and KetalPhos areeffective catalyst for asymmetric allylic alkylation of allylic esters.Table 7 lists some experimental results obtained in this reaction.[Pd(Cl)(C₃H₅)]₂ was used as the catalytic precursor, KOAc and BSA wereused in the reaction. The reactions were run in either CH₂Cl₂ or THF.With chiral ligand 24, up to 91% ee was obtained. Modification ofMe-f-KetalPhos (24) to Et-f-KetalPhos (28) lead to a higher ee (94%). InCH₂Cl₂, Up to 99% ee was achieved with a palladium catalyst bearing theMe-ketalPhos (10) ligand. The yields of these reactions are all over 95%under the reaction conditions.

TABLE 7 Pd. - Catalyzed Asymmetric Allylic Alkylation

Ligand Solvent ee (%) 24 CH₂Cl₂ 91.4 28 CH₂Cl₂ 93.6 28 THF 93.0 10CH₂Cl₂ >99

The foregoing written description relates to various embodiments of thepresent invention. Numerous changes and modifications may be madetherein without departing from the spirit and scope of the invention asdefined in the following claims.

1. A compound of formula C′, or the corresponding enantiomer:

wherein: a) R and R² is independently selected from the group consistingof: aryl, alkyl, alkyl aryl, aryl alkyl, chiral oxazolino which may besubstituted with carboxylic acid, alkoxy, hydroxy, alkylthio, thiol,dialkylamino, or diphenylphosphino groups; of wherein R² is a grouphaving the formula:

wherein Z is a group represented by the formula:

b) R¹ is selected from the group consisting of: H, alkyl, silyl, aryl, awater soluble unit, or a linked polymer chain and an inorganic support;and c)

 is selected from the group consisting of: —(CH₂)_(n)— where n is aninteger ranging from 1 to 8; —(CH₂)_(n)X(CH₂)_(m)— wherein n and m areeach integers, the same or different, ranging from 1 to 8, and X is O,S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl, divalent fused aryl, divalent5-membered ring heterocyclic group, or divalent fused heterocyclicgroup, wherein R⁴ is aryl, alkyl, substituted aryl, or substitutedalkyl; and 1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl or2,2′-divalent 1,2′-binapthyl or ferrocene, each of which may besubstituted with aryl, C₁-C₈ alkyl, F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂,OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, or SbR⁵ ₂; wherein the substitution on1,2-divalent phenyl, the ferrocene or biaryl bridge can be independentlyhalogen, alkyl, alkoxyl, aryl, aryloxy, nitro, amino, vinyl, substitutedvinyl, alkynyl, or sulfonic acids group; and wherein R⁵ is selected froma group consisting of: hydrogen, C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈perfluoroalkyl, aryl, substituted aryl, arylalkyl, ring-substitutedarylalkyl, and —CR³ ₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹ wherein q and p areintegers, the same or different, ranging from 1 to 8; wherein R³ isselected from the group consisting of: aryl, alkyl, substituted aryl,and substituted alkyl; and X is as defined above.
 2. A compoundaccording to claim 1, wherein R is selected from the group consistingof: methyl, ethyl, cyclohexyl, and phenyl; R′ is selected from the groupconsisting of: hydrogen and benzyl; R² is selected from the groupconsisting of: o-X-phenyl wherein X is hydrogen, a carboxylic acid,alkoxy, hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino, anda chiral oxazolino group.
 3. A compound, according to claim 1,represented by formula L28 (C′):


4. A compound according to claim 1 having the following formula or thecorresponding enantiomer:

wherein: A) each R is selected from the group consisting of: C₁-C₈alkyl, C₁-C₈ alkyl aryl, aryl C₁-C₈ alkyl, aryl, each of which may besubstituted with carboxylic acid, alkoxy, hydroxy, C₁-C₈ alkylthio,thiol, dialkylamino, or diphenylphosphino, or chiral oxazoline; and B)each R¹ is selected from the group consisting of: H, C₁-C₈ alkyl,silane, aryl, a water soluble unit, a linked polymer chain and linkedinorganic support; and C) R² is either R, H, or a group having theformula:

wherein

 is selected from the group consisting of: i) —(CH₂)_(n)— where n is aninteger from 1 to 8; ii) —(CH₂)_(n) X (CH₂)_(m)— where n and m are thesame or different integers from 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴,SbR⁴, divalent aryl, divalent fused aryl, divalent 5-memberedheterocyclic ring, or divalent fused heterocyclic ring, where R⁴ isC¹-C⁸ alkyl, aryl, substituted aryl, or substituted C₁-C₈ alkyl; or iii)1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl, 2,2′-divalent, 1,1′binapthyl, or ferrocene, each of which may be substituted independentlywith C₁-C₈ alkyl or aryl, F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵,NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, SbR⁵ ₂, nitro, vinyl, substituted vinyl, alkynylwherein R⁵ is H, C₁-C₈ alkyl, substituted C₁-C₈ alkyl, C₁-C₈fluoroalkyl, C₁-C₈ perfluoroalkyl, aryl or substituted aryl; and wherein Z is a compound selected from the group of compounds having thefollowing formula and its enantiomer:


5. A compound according to claim 4, wherein R is selected from the groupconsisting of: methyl, ethyl, or benzyl; R¹ is selected from the groupconsisting of: hydrogen and benzyl, and

is selected from the group consisting of: —(CH₂)— where n is an integerfrom 1 to 3; 1,2-divalent phenyl, 2,2′ divalent 1,1′ biphenyl,2,2′-divalent 1,2′ binapthyl, and ferrocene, each of which may besubstituted with C₁-C₃ alkyl or OR⁵, wherein R⁵ is methyl or ethyl.
 6. Acompound according to claim 4, represented by the following formula orits enantiomer:


7. A compound according to claim 4, selected from the group of compoundsof the following formulas and its enantiomer:

wherein R is methyl or ethyl.
 8. A compound according to claim 4,selected from the group of compounds of the following formulas and itsenantiomer:

wherein R is either methyl or ethyl.
 9. A compound according to claim 4,selected from the group of compounds of the following formula and itsenantiomer:


10. A catalyst comprising a compound in the form of a complex with atransition metal wherein said compound is selected from compoundsrepresented by the formula;

wherein: a) each R and R² is independently selected from the groupconsisting of: aryl, alkyl, alkyl aryl, aryl alkyl, chiral oxazolinowhich may be substituted with carboxylic acid, alkoxy, hydroxy,alkylthio, thiol, dialkylamino, or diphenylphosphino groups; or whereinR² is a group having the formula:

wherein Z is a group represented by the formula:

b) R¹ is selected from the group consisting of: H, alkyl, silyl, aryl, awater soluble unit, a linked polymer chain and an inorganic support; andc)

 is selected from the group consisting of: —(CH₂)_(n)— where n is aninteger ranging from 1 to 8; —CH₂)_(n)X(CH₂)_(m)— wherein n and m areeach integers, the same or different, ranging from 1 to 8, and X is O,S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl, divalent fused aryl, divalent5-membered ring heterocyclic group, or divalent fused heterocyclicgroup, wherein R⁴ is aryl, alkyl, substituted aryl, or substitutedalkyl; and 1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl or2,2′-divalent 1,2′-binapthyl or ferrocene, each of which may besubstituted with aryl, C₁-C₈ alkyl, F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂,OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, or SbR⁵ ₂; wherein the substitution on1,2-divalent phenyl, the ferrocene or biaryl bridge can be independentlyhalogen, alkyl, alkoxyl, aryl, aryloxy, nitro, amino, vinyl, substitutedvinyl, alkynyl, or sulfonic acid group; and wherein R⁵ is selected fromthe group consisting of: hydrogen, C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈perfluoroalkyl, aryl, substituted aryl, arylalkyl, ring-substitutedarylalkyl, and —CR³ ₂(CR³ ₂)_(g)X(CR³ ₂)_(p)R¹ wherein q and p areintegers, the same or different, ranging from 1 to 8; wherein R³ isselected from the group consisting of: aryl, alkyl, substituted aryl,and substituted alkyl; and X is as defined above.
 11. A catalystaccording to claim 10, wherein the transition metal is selected from thegroup consisting of: rhodium, iridium, ruthenium, nickel, and palladium.12. A catalyst according to claim 11, wherein said compound is a complexwith a compound selected from the group consisting of: Pd₂(DBA)₃,Pd(OAc)₂; [Rh(COD)Cl]₂, [Rh(COD)₂]X, Rh(acac)(CO)₂; RuCl₂(COD),Ru(COD)(methylallyl)₂, Ru(Ar)Cl₂, wherein Ar is an aryl group,unsubstituted or substituted with an alkyl group; [Ir(COD)Cl]₂,[Ir(COD)₂]X; and Ni(allyl)X; wherein X is a counterion.
 13. A catalystaccording to claim 12, wherein X is selected from the group consistingof: F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, ClO₄ ⁻, SbF₆ ⁻, CF₃SO₃ ⁻, and PF₆ ⁻.
 14. Acatalyst according to claim 13, wherein X is PF₆ ⁻.
 15. A catalystaccording to claim 11, wherein the transition metal is Ru or Rh.
 16. Acatalyst according to claim 15, wherein the transition metal is Rh. 17.A catalyst according to claim 10, wherein the catalyst is prepared from:Ru(RCOO)₂(diphosphine), RuX₂(diphosphine),Ru(methylallyl)₂(diphosphine), Ru(aryl group)X₂(diphosphine),Rh(RCOO)₂(diphosphine), RhX₂(diphosphine), Rh(methylallyl)₂ diphosphine,or Rh(aryl group)X₂ (diphosphine) and X is halogen.
 18. A catalystaccording to claim 10, for asymmetric hydrogenation of a ketone, imine,or olefin, comprising: a complex of compounds L28 (C′) or L8 (C′) with aRh compound selected from the group consisting of: [Rh(COD)Cl]₂ and[Rh(COD)₂]X, wherein X is selected from the group consisting of BF₄,ClO₄, SbF₆, CF₃SO₃:


19. A catalyst according to claim 10 comprising a transition metalcomplex of a compound of the following formula or its enantiomer:

wherein: (A) each R is selected from the group consisting of: C₁-C₈alkyl, C₁-C₈ alkyl aryl, aryl C₁-C₈ alkyl, aryl, each of which may besubstituted with carboxylic acid, alkoxy, hydroxy, C₁-C₈ alkylthio,thiol, dialkylamino, diphenylphosphino, and chiral oxazoline; and (B) R¹is selected from the group consisting of: H, C₁-C₈ alkyl, silane, aryl,a water soluble unit, a linked polymer chain and linked inorganicsupport; and (C) R² is either R, H, or a group having the formula:

wherein

 is selected from the group consisting of: (i) —(CH₂)_(n)— where n is aninteger from 1 to 8; or (ii) —(CH₂)_(n)X(CH₂)_(m)— where n and m are thesame or different integers from 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴,SbR⁴, divalent aryl, divalent fused aryl, divalent 5-memberedheterocyclic ring, or divalent fused heterocyclic ring, where R⁴ isC¹-C⁸ alkyl, aryl, substituted aryl, or substituted C₁-C₈ alkyl; or(iii) 1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl, 2,2′-divalent,1,1′ binapthyl, or ferrocene, each of which may be substitutedindependently with C₁-C₈ alkyl or aryl, F, Cl, Br, I, COOR⁵, SO₃R⁵,PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, SbR⁵ ₂, nitro, vinyl,substituted vinyl, alkynyl wherein R⁵ is H, C₁-C₈ alkyl, substitutedC₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈ perfluoroalkyl, aryl orsubstituted aryl; and wherein Z is a compound selected from the group ofcompounds having the following formula and its enantiomer:


20. A catalyst according to claim 10, wherein each R¹ is independentlyselected from the group consisting of: methyl and ethyl groups.
 21. Acatalyst according to claim 10, wherein the transition metal complex isformed from a compound of the following formula or its enantiomer:

and wherein the transition metal is selected from the group consistingof: rhodium, iridium, ruthenium, nickel, and palladium.